Project Summary/Abstract Atrial fibrillation (AF) affects 3-5 million people in the US alone. Although catheter-based procedure is routinely used in treating AF, the high recurrence rate of up to 60 % continues to be a challenge. Over the years it has been shown that the atrial myocardium in AF is associated with fibrosis and this fibrotic substrate is thought to play a major role in sustaining AF. Yet, the goal for most ablation procedures is to electrically isolate the pulmonary veins. This anatomical approach to ablation is based on the assumption that the pulmonary veins are the foci for ectopic activity driving atrial fibrillation shown in paroxysmal AF. More mechanistic approaches based on targeting ?diseased? areas beyond the pulmonary veins, specially, for persistent AF has yielded varying results. This is mostly because (i) there is no good way to identify these diseased areas and (ii) there is no mechanistic understanding of the role played by these fibrotic areas in sustaining AF. More recently, there have been some reports of rotors driving AF. Targeting these rotors has shown some promising early results. The structural basis of these rotors and the mechanism anchoring these to stable sites are still unknown. At the University of Utah we have developed a chronic large animal model of persistent atrial fibrillation. We have also pioneered using MRI to detect atrial wall remodeling in atrial fibrillation but it lacks rigorous histological validation. Using a combination of serial electrical mapping at different resolutions and high resolution in-vivo and ex-vivo MRI proposed here we will develop a more mechanistic approach to catheter-based ablation leading to significant improvement in procedural outcomes. Based on serial high density electrical recording of electrograms processed in both time and frequency domains at different time points in the progression of AF we will develop a detailed mechanistic understanding of AF. These translation studies will show if there are stable drivers of AF and the mechanistic basis for their stability at various locations. These areas of fibrosis that provide stability to AF drivers can be the basis of catheter ablation resulting in an improved outcome. To test this hypothesis, we will make use of unique experimental, clinical and animal model facilities as well as the extensive expertise in electrical mapping, computational modeling and imaging available at University of Utah. The clinical consequence will be reduced number of repeat procedures that are currently done due to arrhythmia recurrence at a significant cost and risk to patients.